Mid-Gestation Maternofetal Inflammation Impacts Growth, Skeletal Muscle Glucose Metabolism, and Inflammatory Tone in the Ovine Fetus During Late Gestation

Authors

Zena Hicks, University of Nebraska-LincolnFollow

First Advisor

Dustin T. Yates

Date of this Version

Summer 7-28-2023

Citation

Hicks, Z.M. 2023. Mid-gestation maternofetal inflammation impacts growth, skeletal muscle glucose metabolism, and inflammatory tone in the ovine fetus during late gestation. Dissertation. University of Nebraska-Lincoln. Available from UNL DigitalCommons.

Comments

A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy, Major: Animal Science (Physiology), Under the Supervision of Professor Dustin T. Yates. Lincoln, Nebraska: August 2023

Copyright © 2023 Zena Mariah Hicks

Abstract

Our 1^st and 2^nd studies assessed the impact of mid-gestation maternofetal inflammation on growth, skeletal muscle glucose metabolism, and inflammatory tone in the late gestation ovine fetus. The objective was to determine if inducing maternofetal inflammation during peak placental growth would lead to more profound IUGR characteristics in the fetus. MI-IUGR fetuses exhibited reduced body and skeletal muscle weights and hallmark asymmetric growth at late gestations. Fetuses had higher baseline glucose:insulin ratios and reduced glucose-stimulated insulin secretion. Moreover, hindlimb glucose oxidation was impaired independent of glucose uptake. Skeletal muscle specific glucose uptake and oxidation was reduced in MI-IUGR fetuses. MI-IUGR fetuses also had increased circulating cytokines and cytokine receptor content in skeletal muscle. Therefore, targeting inflammation during mid- to late gestation is an area of interest for future IUGR therapeutic treatments.

Our 3^rd study examined the differentially expressed genes in neonatal skeletal muscle transcriptome in response to maternofetal inflammation (MI-IUGR) or maternal hyperthermia (PI-IUGR) during gestation. Although PI-IUGR lambs exhibited a more severe IUGR phenotypically, skeletal muscle of MI-IUGR exhibited showed more transcriptomic changes. Regardless of the source of maternal stress, a large percentage of genes and pathways impacted in the IUGR fetus were related to inflammation. These data further support the role of the inflammatory pathway in IUGR pathologies. Our final study examined the changes in tissue composition of the sheep hindlimb across different stages of development. We found that 40% of the tissue in the fetal hindlimb is skeletal muscle compared to 65% of the tissue in the juvenile lamb. This was an important gap in the literature not previously addressed, and could help us more accurately interpret the results of in vivo metabolic studies.

Advisor: Dustin T. Yates